Downregulation of ALKBH5 rejuvenates aged human mesenchymal stem cells and enhances their therapeutic efficacy in myocardial infarction.

Despite promising results in myocardial infarction (MI), mesenchymal stem cell (MSC)-based therapy is limited by cell senescence. N6-methyladenosine (m6A) messenger RNA methylation has been reported to be closely associated with cell senescence. Nonetheless, its role in the regulation of MSC senescence remains unclear. We examined the role of ALKB homolog 5 (ALKBH5) in regulating MSC senescence and determined whether ALKBH5 downregulation could rejuvenate aged MSCs (AMSCs) to improve their therapeutic efficacy for MI. RNA methylation was determined by m6A dot blotting assay. MSC senescence was evaluated by senescence-associated ß-galactosidase (SA-ß-gal) staining. A mouse model of acute MI was established by ligation of the left anterior decedent coronary artery (LAD). Compared with young MSCs (YMSCs), m6A level was significantly reduced but ALKBH5 was greatly increased in AMSCs. Overexpression of ALKBH5 reduced m6A modification and accelerated YMSC senescence. Conversely, ALKBH5 knockdown increased m6A modifications and alleviated AMSC senescence. Mechanistically, ALKBH5 regulated the m6A modification and stability of CDKN1C mRNA, which further upregulated CDKN1C expression, leading to MSC senescence. CDKN1C overexpression ameliorated the inhibition of cellular senescence of ALKBH5 siRNA-treated AMSCs. More importantly, compared with AMSCs, shALKBH5-AMSCs transplantation provided a superior cardioprotective effect against MI in mice by improving MSC survival and angiogenesis. We determined that ALKBH5 accelerated MSC senescence through m6A modification-dependent stabilization of the CDKN1C transcript, providing a potential target for MSC rejuvenation. ALKBH5 knockdown rejuvenated AMSCs and enhanced cardiac function when transplanted into the mouse heart following infarction.

Exosomal miR-9-5p derived from iPSC-MSCs ameliorates doxorubicin-induced cardiomyopathy by inhibiting cardiomyocyte senescence.

Doxorubicin (DOX) is a chemotherapeutic agent widely used for tumor treatment. Nonetheless its clinical application is heavily limited by its cardiotoxicity. There is accumulated evidence that transplantation of mesenchymal stem cell-derived exosomes (MSC-EXOs) can protect against Dox-induced cardiomyopathy (DIC). This study aimed to examine the cardioprotective effects of EXOs isolated from human induced pluripotent stem cell-derived MSCs (iPSC-MSCs) against DIC and explore the potential mechanisms. EXOs were isolated from the cultural supernatant of human BM-MSCs (BM-MSC-EXOs) and iPSC-MSCs (iPSC-MSC-EXOs) by ultracentrifugation. A mouse model of DIC was induced by intraperitoneal injection of Dox followed by tail vein injection of PBS, BM-MSC-EXOs, or iPSC-MSC-EXOs. Cardiac function, cardiomyocyte senescence and mitochondrial dynamics in each group were assessed. In vitro, neonatal mouse cardiomyocytes (NMCMs) were subjected to Dox and treated with BM-MSC-EXOs or iPSC-MSC-EXOs. The mitochondrial morphology and cellular senescence of NMCMs were examined by Mitotracker staining and senescence-associated-ß-galactosidase assay, respectively. Compared with BM-MSC-EXOs, mice treated with iPSC-MSC-EXOs displayed improved cardiac function and decreased cardiomyocyte mitochondrial fragmentation and senescence. In vitro, iPSC-MSC-EXOs were superior to BM-MSC-EXOs in attenuation of cardiomyocyte mitochondrial fragmentation and senescence caused by DOX. MicroRNA sequencing revealed a higher level of miR-9-5p in iPSC-MSC-EXOs than BM-MSC-EXOs. Mechanistically, iPSC-MSC-EXOs transported miR-9-5p into DOX-treated cardiomyocytes, thereby suppressing cardiomyocyte mitochondrial fragmentation and senescence via regulation of the VPO1/ERK signal pathway. These protective effects and cardioprotection against DIC were largely reversed by knockdown of miR-9-5p in iPSC-MSC-EXOs. Our results showed that miR-9-5p transferred by iPSC-MSC-EXOs protected against DIC by alleviating cardiomyocyte senescence via inhibition of the VPO1/ERK pathway. This study offers new insight into the application of iPSC-MSC-EXOs as a novel therapeutic strategy for DIC treatment.

Allocholic acid protects against α-naphthylisothiocyanate-induced cholestasis in mice by ameliorating disordered bile acid homeostasis.

Cholestasis is a pathological condition characterized by disruptions in bile flow, leading to the accumulation of bile acids (BAs) in hepatocytes. Allocholic acid (ACA), a unique fetal BA known for its potent choleretic effects, reappears during liver regeneration and carcinogenesis. In this research, we investigated the protective effects and underlying mechanisms of ACA against mice with cholestasis brought on by α-naphthylisothiocyanate (ANIT). To achieve this, we combined network pharmacology, targeted BA metabolomics, and molecular biology approaches. The results demonstrated that ACA treatment effectively reduced levels of serum AST, ALP, and DBIL, and ameliorated the pathological injury caused by cholestasis. Network pharmacology analysis suggested that ACA primarily regulated BA and salt transport, along with the signaling pathway associated with bile secretion, to improve cholestasis. Subsequently, we examined changes in BA metabolism using UPLC-MS/MS. The findings indicated that ACA pretreatment induced alterations in the size, distribution, and composition of the liver BA pool. Specifically, it reduced the excessive accumulation of BAs, especially cholic acid (CA), taurocholic acid (TCA), and ß-muricholic acid (ß-MCA), facilitating the restoration of BA homeostasis. Furthermore, ACA pretreatment significantly downregulated the expression of hepatic BA synthase Cyp8b1, while enhancing the expression of hepatic efflux transporter Mrp4, as well as the renal efflux transporters Mdr1 and Mrp2. These changes collectively contributed to improved BA efflux from the liver and enhanced renal elimination of BAs. In conclusion, ACA demonstrated its potential to ameliorate ANIT-induced liver damage by inhibiting BA synthesis and promoting both BA efflux and renal elimination pathways, thus, restoring BA homeostasis.

Achieving Long-Enduring High-Voltage Oxygen Redox in P2-Structured Layered Oxide Cathodes by Eliminating Nonlattice Oxygen Redox.

Triggering reversible lattice oxygen redox (LOR) in oxide cathodes is a paradigmatic approach to overcome the capacity ceiling determined by orthodox transition-metal (TM) redox. However, the LOR reactions in P2-structured Na-layered oxides are commonly accompanied by irreversible nonlattice oxygen redox (non-LOR) and large local structural rearrangements, bringing about capacity/voltage fading and constantly evolving charge/discharge voltage curves. Herein, a novel Na0.615 Mg0.154 Ti0.154 Mn0.615 ◻0.077 O2 (◻ = TM vacancies) cathode with both NaOMg and NaO◻ local configurations is deliberately designed. Intriguingly, the activating of oxygen redox at middle-voltage region (2.5-4.1 V) via NaO◻ configuration helps in maintaining the high-voltage plateau from LOR (≈4.38 V) and stable charge/discharge voltage curves even after 100 cycles. Hard X-ray absorption spectroscopy (hXAS), solid-state NMR, and electron paramagnetic resonance studies demonstrate that both the involvement of non-LOR at high-voltage and the structural distortions originating from Jahn-Teller distorted Mn3+ O6 at low-voltage are effectively restrained in Na0.615 Mg0.154 Ti0.154 Mn0.615 ◻0.077 O2 . Resultantly, the P2 phase is well retained in a wide electrochemical window of 1.5-4.5 V (vs Na+ /Na), resulting in an extraordinary capacity retention of 95.2% after 100 cycles. This work defines an effective approach to upgrade the lifespan of Na-ion battery with reversible high-voltage capacity provided by LOR.

Narrow Directed Black Phosphorus Nanoribbons Produced by A Reformative Mechanical Exfoliation Approach.

Black phosphorus nanoribbons (PNRs) are ideal candidates for constructing electronic and optoelectronic devices owing to their unique structure and high bandgap tunability. However, the preparation of high-quality narrow PNRs aligned along the same direction is very challenging. Here, a reformative mechanical exfoliation approach combining tape and polydimethylsiloxane (PDMS) exfoliations to fabricate high-quality, narrow, and directed PNRs with smooth edges for the first time is developed. In this method, partially-exfoliated PNRs are first formed on thick black phosphorus (BP) flakes via the tape exfoliation and further peeled off to obtain separated PNRs via the PDMS exfoliation. The prepared PNRs have widths from a dozen to hundreds of nanometers (down to 15 nm) and a mean length of 18 µm. It is found that the PNRs can align along a same direction and the length directions of directed PNRs are along the zigzag direction. The formation of PNRs is attributed to that the BP prefers to be unzipped along the zigzag direction and has an appropriate magnitude of interaction force with the PDMS substrate. The fabricated PNR/MoS2 heterojunction diode and PNR field-effect transistor exhibit good device performance. This work provides a new pathway to achieve high-quality, narrow, and directed PNRs for electronic and optoelectronic applications.

Safety, efficacy and pharmacokinetics of BPI-9016M in c-MET overexpression or MET exon 14 skipping mutation patients with locally advanced or metastatic non-small-cell lung cancer: a phase Ib study.

BACKGROUND: As a potential target receptor tyrosine kinase, mesenchymal-epithelial transition factor (MET) exhibits high aberrant expression across various tumors. This study aimed to evaluated the safety, tolerability, efficacy and pharmacokinetics (PK) of BPI-9016M, a novel tyrosine kinase inhibitor (TKI) targeting c-MET, in c-MET overexpression or MET exon 14 skipping mutation patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC). METHODS/DESIGN: In this two-part multicenter phase Ib study, eligible patients with locally advanced or metastatic NSCLC harboring c-MET overexpression or MET exon 14 skipping mutation were enrolled into Part A (tested positive for c-MET overexpression [immunohistochemical staining score ≥ 2+]; 300 mg quaque die [QD], 450 mg QD and 600 mg QD cohorts) or Part B (tested positive for MET exon 14 skipping mutation; 400 mg bis in die [BID] cohort), respectively. The primary endpoints were safety, objective response rate (ORR) and disease control rate (DCR), the second endpoints were PK parameters, progression-free survival (PFS) and overall survival (OS). RESULTS: Between March 15, 2017 and September 18, 2021, 38 patients were enrolled (Part A, n = 34; Part B, n = 4). Of 38 patients, 32 (84.2%) patients completed the treatment protocol. As of the data cut-off date on January 27, 2022, all patients reported at least one treatment-emergent adverse event (TEAE). Ninety-two point one percent (35/38) of patients experienced treatment-related adverse events (TRAEs), and grade ≥ 3 TRAEs were observed in 11 (28.9%) patients. The most common TRAEs were elevated alanine aminotransferase (ALT, 14/38, 36.8%) and elevated aspartate aminotransferase (AST, 11/38, 28.9%). Only one (2.6%) patient had treatment-related serious adverse event (SAE) in 600 mg QD cohort due to thrombocytopenia. PK analysis showed BPI-9016M and its main metabolites (M1 and M2-2) reached steady state after seven days of continuous administration. At the dose of 300 mg QD and 450 mg QD, the exposure of BPI-9016M increased with increasing dose. Exposure of BPI-9016M was similar at 450 mg QD and 600 mg QD, which may exhibit a saturation trend. In all patients, ORR and DCR were 2.6% (1/38, 95% confidence interval [CI] 0.1-13.8%) and 42.1% (16/38, 95% CI 26.3-59.2%), respectively. Only one partial response (PR) patient was observed at a dose of 600 mg QD in Part A. In Part B, DCR was 75.0% (3/4, 95% CI 19.4-99.4%). The median PFS and OS in all 38 patients were 1.9 months (95% CI 1.9-3.7) and 10.3 months (95% CI 7.3-not evaluable [NE]), respectively. CONCLUSION: BPI-9016M showed manageable safety profile in c-MET overexpression or MET exon 14 skipping mutation patients with locally advanced or metastatic NSCLC, but showed limited efficacy. TRIAL REGISTRATION: Clinicaltrials.gov NCT02929290 (11/10/2016).

Serum Ionized Calcium as a Prognostic Biomarker in Type B Aortic Dissection After Endovascular Treatment.

OBJECTIVE: Lower serum ionized calcium (iCa2+) was reported to be associated with a higher risk of adverse events in patients with cardiovascular diseases. This study aimed to investigate the associations between preoperative serum iCa2+ and outcomes of type B aortic dissection (TBAD) patients receiving thoracic endovascular aortic repair (TEVAR). METHODS: Between January 2016 and December 2019, 491 TBAD patients received TEVAR in a single center. Patients with acute or subacute TBAD were included. Serum iCa2+ (pH 7.4) was obtained from the arterial blood gas analysis before TEVAR. The study population was grouped into the hi-Ca group (1.11 mmol/L ≤ iCa2+ < 1.35 mmol/L) and lo-Ca group (iCa2+ < 1.11 mmol/L). The primary outcomes were all-cause mortality. The secondary outcomes were any major adverse clinical events (MACEs), which included all-cause mortality and aortic-related severe complications. To eliminate bias, 1:1 propensity score matching (PSM) was conducted. RESULTS: Overall, 396 TBAD patients were included in this study. In the total population, there were 119 (30.1%) patients in the lo-Ca group. After PSM, 77 matched pairs were obtained for further analysis. In the matched population, the 30-day mortality and 30-day MACEs between the two groups presented significant differences (p=0.023 and 0.029, respectively). At 5 years, cumulative incidences of mortality (log-rank p<0.001) and MACEs (log-rank p=0.016) were significantly higher in the lo-Ca group than that of the hi-Ca group. Multivariate cox regression analysis indicated that lower preoperative iCa2+ (hazard ratio for per 0.1 mmol/L decrease, 2.191; 95% confidence interval, 1.487-3.228, p<0.001) was an independent risk factor for 5-year mortality after PSM. CONCLUSIONS: Lower preoperative serum iCa2+ might have an association with 5-year mortality in TBAD patients after TEVAR. Serum iCa2+ monitoring in this population may facilitate the identification of critical conditions. CLINICAL IMPACT: Our present study found that the cutoff value of preoperative serum iCa2+ 1.11 mmol/L, which is slightly lower than the lower limit of the normal range of 1.15-1.35 mmol/L, worked relatively well for discerning the high-risk and low-risk TBAD patients at 5 years. Serum iCa2+ monitoring in TBAD patients receiving TEVAR may facilitate the identification of critical conditions.

Reducing COVID-19 diagnostic errors with dNTPαSe supplementation.

Timely and accurate diagnosis of COVID-19 is critical for controlling the pandemic. As the standard method to diagnose SARS-CoV-2, the real-time reverse transcription polymerase chain reaction (RT-qPCR) has good convenience. However, RT-qPCR still has a relatively high false-negative rate, particularly in the case of detecting low viral loads. In this study, using selenium-modified nucleoside triphosphates (dNTPαSe) in the RT-PCR reactions, we successfully increased the detection sensitivity and reduced the false-negative rate in COVID-19 diagnosis. By detecting positive controls, pseudovirus, and clinical samples with the commercial kits, we found that the dNTPαSe supplementation to these kits could generally offer smaller Ct values, permit the viral detection even in single-digit copies, and increase the detection specificity, sensitivity, and accuracy, thereby reducing the false-negative rate. Our experimental results demonstrated that dNTPαSe supplementation can make the commercial kits more specific, sensitive, and accurate, and this method is a convenient and efficient strategy for the disease detection and diagnosis.

Rotundic acid improves nonalcoholic steatohepatitis in mice by regulating glycolysis and the TLR4/AP1 signaling pathway.

BACKGROUND: Steatosis and inflammation are the hallmarks of nonalcoholic steatohepatitis (NASH). Rotundic acid (RA) is among the key triterpenes of Ilicis Rotundae Cortex and has exhibited multipronged effects in terms of lowering the lipid content and alleviating inflammation. The study objective is to systematically evaluate the potential mechanisms through which RA affects the development and progression of NASH. METHODS: Transcriptomic and proteomic analyses of primary hepatocytes isolated from the control, high-fat diet-induced NASH, and RA treatment groups were performed through Gene Ontology analysis and pathway enrichment. Hub genes were identified through network analysis. Integrative analysis revealed key RA-regulated pathways, which were verified by gene and protein expression studies and cell assays. RESULTS: Hub genes were identified and enriched in the Toll-like receptor 4 (TLR4)/activator protein-1 (AP1) signaling pathway and glycolysis pathway. RA reversed glycolysis and attenuated the TLR4/AP1 pathway, thereby reducing lipid accumulation and inflammation. Additionally, lactate release in L-02 cells increased with NaAsO2-treated and significantly decreased with RA treatment, thus revealing that RA had a major impact on glycolysis. CONCLUSIONS: RA is effective in lowering the lipid content and reducing inflammation in mice with NASH by ameliorating glycolysis and TLR4/AP1 pathways, which contributes to the existing knowledge and potentially sheds light on the development of therapeutic interventions for patients with NASH.

Bifurcation analysis of a free boundary model of vascular tumor growth with a necrotic core and chemotaxis.

A considerable number of research works has been devoted to the study of tumor models. Several biophysical factors, such as cell proliferation, apoptosis, chemotaxis, angiogenesis and necrosis, have been discovered to have an impact on the complicated biological system of tumors. An indicator of the aggressiveness of tumor development is the instability of the shape of the tumor boundary. Complex patterns of tumor morphology have been explored in Lu et al. (J Comput Phys 459:111153, 2022). In this paper, we continue to carry out a bifurcation analysis on such a vascular tumor model with a controlled necrotic core and chemotaxis. This bifurcation analysis, to the parameter of cell proliferation, is built on the explicit formulas of radially symmetric steady-state solutions. By perturbing the tumor free boundary and establishing rigorous estimates of the free boundary system, we prove the existence of the bifurcation branches with Crandall-Rabinowitz theorem. The parameter of chemotaxis is found to influence the monotonicity of the bifurcation point as the mode l increases both theoretically and numerically.

Structural Insight into Polymerase Mechanism via a Chiral Center Generated with a Single Selenium Atom.

DNA synthesis catalyzed by DNA polymerase is essential for all life forms, and phosphodiester bond formation with phosphorus center inversion is a key step in this process. Herein, by using a single-selenium-atom-modified dNTP probe, we report a novel strategy to visualize the reaction stereochemistry and catalysis. We capture the before- and after-reaction states and provide explicit evidence of the center inversion and in-line attacking SN2 mechanism of DNA polymerization, while solving the diastereomer absolute configurations. Further, our kinetic and thermodynamic studies demonstrate that in the presence of Mg2+ ions (or Mn2+), the binding affinity (Km) and reaction selectivity (kcat/Km) of dGTPαSe-Rp were 51.1-fold (or 19.5-fold) stronger and 21.8-fold (or 11.3-fold) higher than those of dGTPαSe-Sp, respectively, indicating that the diastereomeric Se-Sp atom was quite disruptive of the binding and catalysis. Our findings reveal that the third metal ion is much more critical than the other two metal ions in both substrate recognition and bond formation, providing insights into how to better design the polymerase inhibitors and discover the therapeutics.

Single-Atom-Directed Inhibition of De Novo DNA Synthesis in Isothermal Amplifications.

The template-dependent DNA synthesis, with DNA polymerases, templates, and primers, is essential for disease detection, molecular biology, and biotechnology. However, DNA polymerases can also initiate de novo DNA synthesis without templates and primers, forming byproduct DNAs with random sequences. Herein, we report the mechanisms of the de novo DNA synthesis in the absence or presence of nickase by discovering the reduced bindings between the polymerases and modified dNTPs and between the nickases and the modified DNAs and finding the reduced polymerase synthesis and nickase cleavage. Furthermore, via sequencing, we have identified the mechanism of the de novo synthesis in the nickase-based isothermal amplifications, generating the random DNAs as the major byproducts. Fortunately, we have discovered a novel strategy to inhibit the undesired synthesis with the single-atom-modified nucleotides and achieved the accurate and sensitive detection of clinic samples in the isothermal amplifications. In general, we have revealed the suppression mechanisms on the de novo synthesis and demonstrated that this selenium-atom strategy can allow more accurate and sensitive detection of pathogens via the isothermal amplifications.

Symmetry-breaking longitude bifurcations for a free boundary problem modeling small plaques in three dimensions.

Atherosclerosis, one of the leading causes of death in USA and worldwide, begins with a lesion in the intima of the arterial wall, allowing LDL to penetrate into the intima where they are oxidized. The immune system considers these oxidized LDL as a dangerous substance and tasks the macrophages to attack them; incapacitated macrophages become foam cells and leads to the formation of a plaque. As the plaque continues to grow, it progressively restricts the blood flow, possibly triggering heart attack or stroke. Because the blood vessels tend to be circular, two-space dimensional cross section model is a good approximation, and the two-space dimensional models are studied in Friedman et al. (J Differ Equ 259(4):1227-1255, 2015) and Zhao and Hu (J Differ Equ 288:250-287, 2021). It is interesting to see whether a true three-space dimensional stationary solution can be developed. We shall establish a three-space dimensional stationary solution for the mathematical model of the initiation and development of atherosclerosis which involves LDL and HDL cholesterols, macrophages and foam cells. The model is a highly nonlinear and coupled system of PDEs with a free boundary, the interface between the plaque and the blood flow. We establish infinite branches of symmetry-breaking stationary solutions which bifurcate from the annular stationary solution in the longitude direction.

Nickel oxide nanoparticles induce apoptosis and ferroptosis in airway epithelial cells via ATF3.

Exposure to nickel oxide nanoparticles (NiONPs), which have been widely produced and applied in industry, leads to adverse pulmonary and systemic effects. The aim of this study is to investigate the involvement of apoptosis and ferroptosis in NiONPs-induced acute lung injury (ALI). Intratracheal instillation of NiONPs into mice elevated the levels of pro-inflammatory cytokines, neutrophils, and proteins in the bronchoalveolar lavage fluid, and triggered apoptosis and ferroptosis in the lung tissues. Consistently, NiONPs-induced apoptosis and ferroptosis were observed in in vitro experiments using human lung epithelial cells. Activating transcription factor 3 (ATF3), a stress-inducible transcription factor, was upregulated by NiONPs exposure in both murine lung tissues and human lung epithelial cells. Moreover, human lung epithelial cells with ATF3 deficiency exhibited a lower level of apoptosis and ferroptosis when exposed to NiONPs. Collectively, our findings demonstrated that ATF3 was responsive to NiONPs exposure, and promoted NiONPs-induced apoptosis and ferroptosis in lung epithelial cells, indicating that ATF3 is a potential biomarker and therapeutic target for NiONPs-associated ALI.

Gravity, Quantum Fields and Quantum Information: Problems with Classical Channel and Stochastic Theories.

In recent years an increasing number of papers have attempted to mimic or supplant quantum field theory in discussions of issues related to gravity by the tools and through the perspective of quantum information theory, often in the context of alternative quantum theories. In this article, we point out three common problems in such treatments. First, we show that the notion of interactions mediated by an information channel is not, in general, equivalent to the treatment of interactions by quantum field theory. When used to describe gravity, this notion may lead to inconsistencies with general relativity. Second, we point out that in general one cannot replace a quantum field by a classical stochastic field, or mock up the effects of quantum fluctuations by that of classical stochastic sources (noises), because in so doing important quantum features such as coherence and entanglement will be left out. Third, we explain how under specific conditions semi-classical and stochastic theories indeed can be formulated from their quantum origins and play a role at certain regimes of interest.

Quantum Thermodynamic Uncertainty Relations, Generalized Current Fluctuations and Nonequilibrium Fluctuation-Dissipation Inequalities.

Thermodynamic uncertainty relations (TURs) represent one of the few broad-based and fundamental relations in our toolbox for tackling the thermodynamics of nonequilibrium systems. One form of TUR quantifies the minimal energetic cost of achieving a certain precision in determining a nonequilibrium current. In this initial stage of our research program, our goal is to provide the quantum theoretical basis of TURs using microphysics models of linear open quantum systems where it is possible to obtain exact solutions. In paper [Dong et al., Entropy 2022, 24, 870], we show how TURs are rooted in the quantum uncertainty principles and the fluctuation-dissipation inequalities (FDI) under fully nonequilibrium conditions. In this paper, we shift our attention from the quantum basis to the thermal manifests. Using a microscopic model for the bath's spectral density in quantum Brownian motion studies, we formulate a "thermal" FDI in the quantum nonequilibrium dynamics which is valid at high temperatures. This brings the quantum TURs we derive here to the classical domain and can thus be compared with some popular forms of TURs. In the thermal-energy-dominated regimes, our FDIs provide better estimates on the uncertainty of thermodynamic quantities. Our treatment includes full back-action from the environment onto the system. As a concrete example of the generalized current, we examine the energy flux or power entering the Brownian particle and find an exact expression of the corresponding current-current correlations. In so doing, we show that the statistical properties of the bath and the causality of the system+bath interaction both enter into the TURs obeyed by the thermodynamic quantities.

Entanglement Dynamics of Coupled Quantum Oscillators in Independent NonMarkovian Baths.

This work strives to better understand how the entanglement in an open quantum system, here represented by two coupled Brownian oscillators, is affected by a nonMarkovian environment (with memories), here represented by two independent baths each oscillator separately interacts with. We consider two settings, a 'symmetric' configuration wherein the parameters of both oscillators and their baths are identical, and an 'asymmetric' configuration wherein they are different, in particular, a 'hybrid' configuration, where one of the two coupled oscillators interacts with a nonMarkovian bath and the other with a Markovian bath. Upon finding the solutions to the Langevin equations governing the system dynamics and the evolution of the covariance matrix elements entering into its entanglement dynamics, we ask two groups of questions: (Q1) Which time regime does the bath's nonMarkovianity benefit the system's entanglement most? The answers we get from detailed numerical studies suggest that (A1) For an initially entangled pair of oscillators, we see that in the intermediate time range, the duration of entanglement is proportional to the memory time, and it lasts a fraction of the relaxation time, but at late times when the dynamics reaches a steady state, the value of the symplectic eigenvalue of the partially transposed covariance matrix barely benefit from the bath nonMarkovianity. For the second group of questions: (Q2) Can the memory of one nonMarkovian bath be passed on to another Markovian bath? And if so, does this memory transfer help to sustain the system's entanglement dynamics? Our results from numerical studies of the asymmetric hybrid configuration indicate that (A2) A system with a short memory time can acquire improvement when it is coupled to another system with a long memory time, but, at a cost of the latter. The sustainability of the bipartite entanglement is determined by the party which breaks off entanglement most easily.

Quantum Thermodynamic Uncertainties in Nonequilibrium Systems from Robertson-Schrödinger Relations.

Thermodynamic uncertainty principles make up one of the few rare anchors in the largely uncharted waters of nonequilibrium systems, the fluctuation theorems being the more familiar. In this work we aim to trace the uncertainties of thermodynamic quantities in nonequilibrium systems to their quantum origins, namely, to the quantum uncertainty principles. Our results enable us to make this categorical statement: For Gaussian systems, thermodynamic functions are functionals of the Robertson-Schrödinger uncertainty function, which is always non-negative for quantum systems, but not necessarily so for classical systems. Here, quantum refers to noncommutativity of the canonical operator pairs. From the nonequilibrium free energy, we succeeded in deriving several inequalities between certain thermodynamic quantities. They assume the same forms as those in conventional thermodynamics, but these are nonequilibrium in nature and they hold for all times and at strong coupling. In addition we show that a fluctuation-dissipation inequality exists at all times in the nonequilibrium dynamics of the system. For nonequilibrium systems which relax to an equilibrium state at late times, this fluctuation-dissipation inequality leads to the Robertson-Schrödinger uncertainty principle with the help of the Cauchy-Schwarz inequality. This work provides the microscopic quantum basis to certain important thermodynamic properties of macroscopic nonequilibrium systems.

MicroRNA-199a-5p aggravates angiotensin II-induced vascular smooth muscle cell senescence by targeting Sirtuin-1 in abdominal aortic aneurysm.

Vascular smooth muscle cells (VSMCs) senescence contributes to abdominal aortic aneurysm (AAA) formation although the underlying mechanisms remain unclear. This study aimed to investigate the role of miR-199a-5p in regulating VSMC senescence in AAA. VSMC senescence was determined by a senescence-associated ß-galactosidase (SA-ß-gal) assay. RT-PCR and Western blotting were performed to measure miRNA and protein level, respectively. The generation of reactive oxygen species (ROS) was evaluated by H2DCFDA staining. Dual-luciferase reporter assay was used to validate the target gene of miR-199a-5p. VSMCs exhibited increased senescence in AAA tissue relative to healthy aortic tissue from control donors. Compared with VSMCs isolated from control donors (control-VSMCs), those derived from patients with AAA (AAA-VSMCs) exhibited increased cellular senescence and ROS production. Angiotensin II (Ang II) induced VSMC senescence by promoting ROS generation. The level of miR-199a-5p expression was upregulated in the plasma from AAA patients and Ang II-treated VSMCs. Mechanistically, Ang II treatment significantly elevated miR-199a-5p level, thereby stimulating ROS generation by repressing Sirt1 and consequent VSMC senescence. Nevertheless, Ang II-induced VSMC senescence was partially attenuated by a miR-199a-5p inhibitor or Sirt1 activator. Our study revealed that miR-199a-5p aggravates Ang II-induced VSMC senescence by targeting Sirt1 and that miR-199a-5p is a potential therapeutic target for AAA.

Equal access to care and nurse navigation leads to equitable outcomes for minorities with aggressive large B-cell lymphoma.

BACKGROUND: Aggressive large B-cell lymphomas (LBCLs) are curable, but previous studies have shown inferior outcomes in minorities. Nurse navigation programs can improve patient outcomes by providing patient support. This study presents the outcomes of White and minority patients with aggressive LBCL at an institution with an active nurse navigation program. METHODS: The authors prospectively collected baseline characteristics, treatment regimens, and outcome data for patients with aggressive LBCL. Navigation encounters were characterized as low or high intensity. Overall survival (OS) and progression-free survival (PFS) were calculated with Kaplan-Meier methods. Baseline characteristics were compared with Fisher exact tests. RESULTS: Two hundred four consecutive patients (47 minority patients and 157 White patients) were included. Results were presented as minorities versus Whites. There were no differences in prognostic scores (Revised International Prognostic Index score of 3-5, 43% vs 47%; P = .50), frontline chemotherapy (98% vs 96%; P = .68), or the incidence of relapsed/refractory disease (40% vs 38%; P = .74). For relapsed/refractory LBCL, similar proportions of patients underwent hematopoietic stem cell transplantation (32% vs 29%; P > .99) or chimeric antigen receptor T-cell therapy (16% vs 19%; P > .99). Enrollment in clinical trials was comparable (17% vs 14%; P = .64). More than 85% received nurse navigation, but minorities had higher intensity navigation encounters (42% vs 21%; P = .01). The 2-year OS rates were 81% and 76% for minorities and Whites, respectively (P = .27); the 2-year PFS rates were 62% and 65%, respectively (P = .78). CONCLUSIONS: This study shows similar survival between Whites and minorities with aggressive LBCL, which was likely due to equal access to guideline-concordant therapy. Minorities received higher intensity navigation encounters, which may have helped them to overcome socioeconomic disadvantages.